The present invention is directed to the use of certain racemic and optically active pyrido[1,2-a]-pyrazine derivatives, also described as bis-azabicyclic compounds and defined by the formula (I) below in the treatment of abuse of and addiction to such substances as narcotics, alcohol, nicotine and amphetamines. The compounds of the formula (I) and their use in the treatment of anxiety and depression are the subjects of copending International application nos. PCT/US89/00275, filed Jan. 26, 1989, and PCT/US89/03811, filed Sep. 1, 1989.
Recently a number of 1-(2-pyrimidinyl)-4-[4-(cyclic-imido)butyl]piperidine derivatives have been disclosed as anxiolytic agents which are generally lacking sedative activity. Among these are buspirone, where the cyclic-imido group is 4,4-tetramethylene-piperidine-2,6-dion-1-yl (Wu et al., U.S. Pat. Nos. 3,717,634 and 3,907,801; Casten et al., U.S. Pat. Nos. 4,182,763); gepirone, where the group is 4,4-dimethylpiperidine-2,6-dion-1-yl (Temple, Jr., U.S. Pat. No. 4,423,049); and ipsapirone, where the group is 1,1-dioxobenzo[d]isothiazol-3(2H)-on-2-yl (Dompert et al., German patent publication 3,321,969-Al). See also Ishizumi et al., U.S. Pat. Nos. 4,507,303 and 4,543,355; Freed et al., U.S. Pat. 4,562,255; Stack et al., U.S. Pat. No. 4,732,983; New et al., U.S. Pat. No. 4,524,026; and Stack, U.S. Pat. No. 4,788,290.
Such agents as busipirone and gepirone have now been shown to possess antidepressant activity [Schweizer et al., Psychopharm. Bull., v. 22, pp. 183-185 (1986); Amsterdam et al., Current. Therap. Res., v. 41, pp. 185-193 (1987); and Stack, U.S. Pat. No. 4,788,290]; and most recently, to be of value in the treatment of substance addiction, such as over-eating, tobacco addiction and drug abuse (published European patent application EP-A-356,997).
The present bis-aza-bicyclic compounds generally show minimal in vivo stimulation of dopaminergic systems, reflective of reduced or minimal neurological side effects in the clinical use of these compounds.